Cytotoxic & MDR-Active Alkaloids-Synthesis & Evaluation

描述(申请人提供)：本研究项目的主要目标是以对映体纯形式合成重氮酰胺A(修订结构，1)和N-甲基韦林酮C异硫氰酸酯(2)。具体目标将集中在六个挑战上：1.第一个目标是在C10/C11中心高效地合成所需的立体化学，作为导致重氮酰胺A的高级片段。芳基铅(IV)化合物是一种高选择性和温和的试剂，用于生成四元中心。我们在这方面的研究特别有成效。2.第二个目标是进行有效的芳基-芳基偶联反应，以建立C16/C18键。有机金属技术可以用来进行芳基-芳基偶联反应。文献中存在许多这样的例子，我们自己的研究也同意这一评估。3.第三个目标是有效地合成双恶唑体系，同时生成重氮酰胺A的大双环结构。N-酰基-D-氨基酮的环脱水将有效地生成C29到C31恶唑，而C26到C28氯恶唑可以通过[32]环加成策略有效地合成。4.第四个目标是高效地合成N-甲基韦林酮C异硫氰酸酯的整个环系。C3和C16之间的分子内共轭加成反应，再加上吲哚C4位与C11的有效分子间偶联，将有效地生成2.5的中心七元环。第五个目标是成功地合成N-甲基韦林酮C异硫氰酸酯中的C11/C12立体中心阵列。从C11直接引入C12的功能将允许两个中心同时开发。6.第六个具体目标是合成这两个目标的选定衍生物，用于生物测试和评价。测试方面的合作已经建立。重氮酰胺A是一种细胞毒剂，N甲基韦林酮C异硫氰酸酯是一种多药耐药逆转剂。只有对这些天然产物和选定的衍生品进行积极的合成计划，才能全面检查它们作为细胞周期研究的生物制剂和可能的治疗方法。

DESCRIPTION (provided by applicant): The principle objectives of this research project are the synthesis, in enantiomerically pure form, of diazonamide A (revised structure, 1) and N-methylwelwitindolinone C isothiocyanate (2). The specific aims will focus on six challenges: 1. The first aim is an efficient synthesis of the desired stereochemistry at the C10/C11 centers as an advanced fragment leading to diazonamide A. Aryllead(IV) compounds are highly selective and mild reagents for the production of quaternary centers. Our studies in this area have been especially fruitful. 2. The second aim is the execution of an effective aryl-aryl coupling reaction to set the C16/C18 bond. Organometallic technology can be employed to perform this aryl-aryl coupling reaction. Many such examples exist in the literature, and our own studies concur with this assessment. 3. The third aim is the efficient synthesis of the bis-oxazole system in conjunction with generation of the macrobicyclic structure of diazonamide A. Cyclodehydration of a N-acyI-D-aminoketone will effectively generate the C29 through C31 oxazole, whereas the C26 through C28 chlorooxazole can be effectively prepared via a [3+2] cycloaddition strategy. 4. The fourth aim is the efficient synthesis of the entire ring system of N-methylwelwitindolinone C isothiocyanate. An intramolecular conjugate addition reaction between C3 and C16, coupled with an efficient intermolecular coupling of the indole C4 position with C11, will efficiently generate the central sevenmembered ring of 2. 5. The fifth aim is the successful synthesis of the C11/C12 array of stereocenters in Nmethylwelwitindolinone C isothiocyanate. Directed introduction of functionality at C12 from C11 will allow both centers to be developed simultaneously. 6. The sixth specific aim is the synthesis of selected derivatives of both these targets for biological testing and evaluation. Collaborations for testing have been established. Diazonamide A is a cytotoxic agent and Nmethylwelwitindolinone C isothiocyanate is a multidrug resistance (MDR) reversal agent. Only a vigorous synthetic program toward these natural products and selected derivatives will allow for their full examination both as biological agents for cell cycle study and as possible therapeutics.